Asymmetric addition of organometallic compounds to carbonyls is a useful method for the production of chiral secondary/tertiary-alcohols. Typically for asymmetric synthesis, the active catalyst is generated in situ by the reaction of Lewis acid with chiral ligands. Addition of organometallic reagents to aldehydes and activated ketones has been achieved with excellent enantioselectivity. With inactivated ketones there has been some success, e.g., using salen 1 and camphanosulphonamide ligand 2.

Generally, stoichiometric amount of the promoters [Lewis acid, e.g., ZnR2 (R=alkyl/aryl), Zn(OTf)2, Cu(OTf)2, etc] is required for these asymmetric syntheses. Although, employing these promoters, chiral alcohols has been obtained in high yields and ee upto 99%, they have limited applicability in industrial scale synthesis of the pharmaceutical intermediates, because they are expensive, difficult to store, difficult to handle, especially dialkyl zinc as disclosed in U.S. Pat. No. 5,952,528 (“the '528 patent”) and U.S. Pat. No. 6,015,926 (“the '926 patent”) are highly pyrophoric and require special modification to transfer the reagent. Moreover the liberated byproducts methane/ethane (when using ZnMe2/ZnEt2) is a concern on industrial scale synthesis.
The '528 patent and the '926 patent discloses an efficient process for chiral amino alcohol by addition of n-butyl lithium and cyclopropylacetylene to a ketone in presence of a chiral organozinc complex comprising of chiral additive and dialkyl zinc. Alternatively, adding chloromagnesium complex of cyclopropylacetylene to the ketone in presence of the chiral organozinc complex. The synthesis disclosed is schematically represented as follows:

The '926 patent further discloses preparation of chloromagnesium complex of cyclopropylacetylene by reaction of cyclopropylacetylene and Grignard reagent (n-alkyl magnesium chloride). Grignard reactions are highly sensitive to moisture and utmost care to store and use; it requires high volumes of solvent medium for complex formation. This in turn results to utilization of additional manufacturing steps and requires increase in the equipment capacity, particularly on commercial scale.
Patent publication No. WO 2001/70707 (“the '707 publication”) discloses an asymmetric process for preparing chiral amino alcohol via chiral ligand mediated asymmetric addition in presence of a large excess of strong lithium base such as n-butyl lithium and LHMDS and excess of chiral moderator.
Patent publication No. WO 96/37457 (“the '457 publication”) discloses asymmetric process for preparing chiral amino alcohol by providing a mixture of excess chiral additive with an excess of cyclopropylacetylene and an excess of alkyl lithium followed by mixing it with a ketone at a temperature of about −78° C. to about −20° C.
Although alkyl lithium is frequently used to carry out the aforementioned reaction, it is both expensive and pyrophoric. Thus, alkyl lithium is not an ideal reagent because its use increases costs of production and presents significant safety hazards for users unfamiliar with the handling of pyrophoric materials.
U.S. Pat. No. 7,439,400 (“the '400 patent”) discloses a process for the preparation of chiral proparglic alcohol or chiral proparglic amine by first preparing chiral organometallic complex comprising chiral compound, zinc or copper salts such as halides or triflates in presence of organic base such as triethylamine and neat cyclopropylacetylene. The chiral organometallic complex is then mixed with a ketone or ketimine to obtain the chiral proparglic alcohol or chiral proparglic amine. The synthesis disclosed is schematically represented as follows:

The '400 patent has the following drawbacks, such as:
i) The product, chiral proparglic alcohol or amine obtained are low to moderate yields,
ii) It involves zinc/copper triflates during the formation of chiral zincate complex. These have certain limitations such as a) limited commercial availability, b) expensive reagents, c) difficult to transport, handle and store as these have moisture sensitive, andiii) Besides this, for use of zinc/copper halides, the nucleophilic displacement of halogens from zinc/copper halides is not feasible with the organic bases.
In view of the limitations associated with the methods of producing chiral amino alcohols, there is a need for an efficient process to induce enantioselectivity in procarbonyl compounds with improved yields without using expensive reagents like n-butyl lithium and dialkyl zinc and avoids precarious Grignard reactions, and a simple, reproducible and straightforward method of producing such a product, which can be carried out using variety of reagents such as inexpensive zinc/copper salts to replacing the expensive and explosive dialkyl zinc for preparing chiral organometallic complex; and using a base and a metal salt for preparing terminal alkyne complex to avoiding the precarious Grignard reactions. The present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield and enantioselectivity.
Our co-pending Patent application 262/CHE/2008 (“the '262 publication”) discloses a process for preparing chiral amino alcohol via preparing an organometallic complex such as organozinc complex comprising the steps of: a) preparing salts of mixture of chiral additive and achiral additive with an inorganic base, b) adding metal halides such as zinc halides to the salts of mixture of chiral additive and achiral additive to obtain the chiral zincate complex, c) adding lithium or magnesium cyclopropylacetylide complex to the chiral zincate complex to obtain chiral organozinc alkyne complex and d) mixing ketone with the chiral organozinc complex. The synthesis disclosed in the '262 publication is schematically represented as follows:

The advantages associated with the '262 publication include the use of low cost zinc/copper halides are ease of storing, handling and transfer, moreover, the byproducts (sodium salts) formed has no safety concerns.
The present invention has certain improvements over the '262 publication such as use of other zinc/copper salts for forming chiral metal complex and avoids precarious Grignard reactions, therefore usage of large volume of reaction solvent and large capacity of equipment is minimized.
The process of the present invention can be utilized with other active catalysts using chiral additives such as binols, amino alcohols and its derivatives, ethylene diamine and its derivatives in combination with zinc/copper salts.